1. Kytril: a once-daily 5HT 3 receptor antagonist for control of chemotherapy-induced nausea and vomiting (CINV) Frederick Schnell Central Georgia Hematology Oncology Associates Macon, GA, USA

2. Nausea and vomiting significantly impact on patients’ quality of life 1 Following chemotherapy †, nausea/vomiting scored by patients (n=80) using 5-day diary and 6-day Functional Living Index Doctors and nurses (n=9) estimated frequency of acute and delayed nausea/vomiting Physicians/nurses (estimate) Patients (actual) Acute (%) 6953 no nausea no vomiting8372 Delayed (%) no nausea7643 no vomiting9159 1. Grunberg. Proc Am Soc Clin Oncol 2002;21:250a (Abstract 996) † First-cycle moderately emetogenic chemotherapy

3. Nausea and vomiting are rated as major side-effects of cancer therapy Following the introduction of 5HT 3 receptor antagonists, the rating of vomiting as a side-effect of chemotherapy has declined 2,3 Rank1983 1 1995 2 1VomitingNausea 2 Alopecia 3 Vomiting 1. Coates et al. Eur J Cancer Clin Oncol 1983;19:203–8 2. de Boer-Dennert et al. Br J Cancer 1997;76:1055–61 3. Griffin et al. Ann Oncol 1996;7:189–95

4. Pharmacologic control of vomiting Pharmacologic prevention of vomiting is directed at blocking vomiting pathways before the administration of chemotherapy or radiotherapy treatments Antiemetics may act via the: 1 –vomiting center –chemoreceptor trigger zone –peripheral receptors (e.g. vagal afferent nerves) 1. Lindley, Blower. Am J Health-Syst Pharm 2000;57:1685–97

5. Which antiemetic? Commonly used agents include: –dopamine-receptor antagonists –corticosteroids –benzodiazepines –antihistamines –5HT 3 -receptor antagonists 5HT 3 -receptor antagonists are currently the ‘gold-standard’ antiemetic 1–4 1. Gralla et al. J Clin Oncol 1999;17:2971–94 2. ASHP. Am J Health-Syst Pharm 1999;56:729–64 3. MASCC. Ann Oncol 1998;9:811–19 4. Koeller et al. Support Care Cancer 2002;10:514–22

6. Optimizing antiemetic treatment Awareness must be increased for: –current guidelines –evidence supporting guideline recommendations –incidence of and risk factors for nausea and vomiting Antiemetic treatment must be individualized based on patients’ cytotoxic treatment and patient-specific factors

7. Antiemetic guidelines Differences exist in antiemetic guidelines –ASCO (American Society of Clinical Oncology) –MASCC (Multinational Association of Supportive Care in Cancer) –ASHP (American Society of Health-Systems Pharmacists) Need easy-to-follow, comprehensive consensus guidelines Need guidelines from radiation experts that address needs of radiation therapy patients

8. Patients need less complicated, effective antiemetic therapy The majority of cancer patients receiving radiotherapy are elderly out-patients –require fast-acting, long-duration oral antiemetics Convenient once-daily oral dosing should: –  patient compliance –  control of nausea and vomiting –  patient quality of life

9. Who is the ‘average’ cancer patient? Cancer incidence and mortality greatest in elderly patients 1 –‘average’ patient >65 years 2 –increased incidence of co-morbidities with aging (>3.6 in patients aged >65 years) 3 –increased use of concomitant medications in patients >65 years (average medications=4.3 per person) 4 1. Yancik, Ries. Hematol Oncol Clin North Am 2000;14:17–23 2. Yancik et al. J Clin Oncol 2001;19:1147–51 3. Yancik. Cancer 1997;80:1273–83 4. Jorgensen et al. Ann Pharmacother 2001;35:1004–9

10. Chemotherapy- and radiation-induced emesis in the elderly Elderly are more likely to suffer from chemotherapy and radiotherapy-induced toxicity 1 –may have declining organ function –co-morbidities –concomitant medications 2,3 Consequences of nausea and vomiting can be exacerbated in elderly, mainly in patients with co-morbidities –dehydration in patients taking diuretics –exacerbation of cognitive problems –falls due to extra-pyramidal effects 1. Extermann et al. Hematol Oncol Clin North Am 2000;14:63–77 2. Jorgensen et al. Ann Pharmacother 2001;35:1004–9 3. Hanlon et al. Drugs Aging 2001

11. Suboptimal antiemetic treatment in the elderly Older patients may receive suboptimal antiemetic treatment because of: –gastrointestinal changes 1 – decreased drug absorption –contraindications to corticosteroids (e.g. with hypertension, diabetes) 2 –swallowing problems 1,3 –noncompliance to oral therapies 4 –possible cognitive impairment/confusion 5 Patients need a single drug intake per day 1. Orr, Chen. Am J Physiol Gastrointest Liver Physiol 2002;283:G1226–31 2. http://www.geriatricsyllabus.com/syllabus/main.jsp?cid=SCC-DER-4-2 3. Wilkinson, de Picciotto. S Afr J Commun Disord 1999;46:55–64 4. Lebovits et al. Cancer 1990;65:17–22; 5. Schroder et al. J Neural Transm Suppl 1998;54:51–9

12. Which 5-HT 3 -receptor antagonist? Kytril (granisetron) and ondansetron are currently indicated for CINV and radiotherapy-induced nausea and vomiting (RINV) Differences exist between Kytril and ondansetron –underlying pharmacology –duration of efficacy –hepatic metabolism –dose adjustments in hepatically impaired patients –dosing regimens

13. Drug-drug interactions Kytril –not shown to induce or inhibit hepatic metabolism 1 –only 5-HT 3 -receptor antagonist not linked to CYP2D6 genetic polymorphism 1 Ondansetron –known interactions chemotherapeutic agents 2 antidepressants 3 antibiotics 4,5 analgesics 6 1. Blower. Cancer J 2002;8:405–14; 2.Cagnoni et al. BMT 1999;24:1–4 3. Stanford, Stanford. J Psychopharmacol 1999;13:313–7 4. www.hivmedicationguide.com/Asp_bin/drug%20interactions.asp 5. www.anaesthetist.com/physiol/basics/metabol/cyp/o.htm 6. DeWitte et al. Anesth Analg 2001;92:1319–21

14. Hepatic metabolism route Kytril has not been shown to induce or inhibit hepatic metabolism 1 CYP1A1CYP1A2CYP2D6CYP3A3/4/5 Granisetron  Ondansetron **  Dolasetron  Tropisetron  * * *Minor 1. Bower. Cancer J 2002;8:405–14

15. CYP2D6 polymorphism Genetic polymorphism shown to affect cancer patients’ response to ondansetron and tropisetron therapy 1 Kytril not at risk for genetic polymorphism –genetic testing required to determine true risk AE = adverse event Ultra-rapid metabolizers (enzyme induction)  Metabolism  Efficacy Poor metabolizers (enzyme inhibition)  Metabolism  Risk of AEs 1. Kaiser et al. J Clin Oncol 2002;20:2805–11

16. Cardiovascular warning (prescribing information) Kytril 1  Ondansetron 2  Dolasetron 3  Tropisetron 4  Cardiovascular warnings 1. Kytril (granisetron hydrochloride) Prescribing Information 2. Zofran (ondansetron hydrochloride) Prescribing Information 3. Anzemet (dolasetron mesylate) Prescribing information 4. Navoban (tropisetron) Prescribing Information

17. Cardiotoxic effects of 5-HT 3 -receptor antagonists in healthy adults AgentDoseECG changesClinical effects Kytril 1 10 µg/kg, i.v. (5 min)No differencesNot clinically significant Ondansetron 1 10 µg/kg, i.v. (30 s) 32 mg, i.v. (15 min)  mean post-dose QTc interval* Dolasetron 2 1.2, 1.8, 2.4 mg/kg, i.v.  PR, QTc, QRS intervals** Dose-related  in heart rate Ondansetron 2 32 mg, i.v.  QTc* & JT** intervals  in heart rate Kytril 3 2 mg, p.o.Isolated ventricular & supraventricular ectopic activity No sustained arrhythmias Dolasetron 4 0.6–5.0 mg/kg, i.v.  PR interval & QRS duration  heart rate at 3 mg/kg or over *p<0.05; **p<0.001 1. Boike et al. Am J Health-Syst Pharm 1997;54:1172–6 2. Benedict et al. J Cardiovasc Pharmacol 1996;28:53–9 3. Gray et al. Aviat Space Environ Med 1996;67:759–61 4. Hunt et al. J Clin Pharmacol 1995;35:705–12

18. Dosing regimen: Kytril vs ondansetron Ondansetron dosed 2–3 times daily –associated with swallowing problems when patients are nauseated Once-daily Kytril dosing –  patient compliance –  patient quality of life

19. Antiemetic therapy decisions Therapy should depend on the unique needs of each patient: –age/health –co-morbidities –concomitant medications Physicians need to be aware that differences exist between the available 5HT 3 -receptor antagonists

20. A rational choice in the elderly Co-morbidity assessment Polypharmacy Drug–drug interactions Antiemetic selection that limits complications Reduced risk of toxicity Increased possibility of clinical efficacy

21. Kytril vs ‘conventional’/older antiemetics Double-blind, placebo-controlled trial 30 patients undergoing single-fraction total body irradiation (7.5 Gy) received i.v.: –Kytril, 3 mg ‡ –metoclopramide (20 mg), dexamethasone (6 mg/m 2 ), lorazepam (2 mg), 1 hour prior to radiotherapy KytrilComparatorp value Complete response* rate53%13%0.02 No vomiting rate (24 hours) 60%13%0.008 *No vomiting, no more than mild nausea and no rescue medication ‡ Off-label dose in the USA 1. Prentice et al. Bone Marrow Transplant 1995;15:445–8

22. Kytril is effective in patients refractory to ‘conventional’ antiemetics Patients (n=15) refractory to treatment with dopamine- receptor antagonists were scheduled to receive Kytril, 1 mg/day p.o., ‡ 1–2 hours prior to further radiotherapy* Results of Kytril therapy –complete remission of symptoms was observed in all patients on days 1–3 –immediate remission of nausea and vomiting was apparent in 33% of patients *Pelvic, lumboaortic ± iliac/splenic regions or mediastinum radiotherapy ‡ Off-label dose 1. Krengli et al. Minerva Med 1996;87:605–8

23. Kytril vs tropisetron in pediatric cancer patients 0 20 40 60 80 100 VomitingNausea Kytril tropisetron Patients (%) 88 82 74 56 p<0.05 p<0.002 Aksoylar et al. Pediatr Hematol Oncol 2001;18:397–406

24. Kytril is well tolerated – adverse events classed as mild and transient Most frequently reported adverse events in clinical trials with Kytril Occurrence EventKytril 1 comparator 2 placebo 3 Headache20%13%12% Asthenia18%10%4% Constipation14%16%8% Diarrhea9%10%4% Dyspepsia6%5%4% Abdominal pain4%6%3% Kytril Prescribing Information, chemotherapy data 1 2 mg p.o. q.d. (n=1450); 2 Metochlopramide/dexamethasone; phenothiazines/ dexamethasone; dexamethasone alone; prochlorperazine (n=599); 3 (n=185)

25. RINV – a significant clinical problem Over 80% of patients undergoing radiation of the upper torso will experience nausea and vomiting 1 Fractionated radiotherapy may involve up to 40 fractions over 6–8 weeks, resulting in prolonged symptoms of emesis 2 Uncontrolled nausea and vomiting may lead patients to delay or refuse future radiotherapy 3 1. Danioux et al. Clin Radiol 1979;30:581–4 2. Feyer et al. Support Care Cancer 1998;6:253–60 3. Laszlo. In: Antiemetics and Cancer Chemotherapy, 1983:1–5

26. Incidence of nausea and vomiting Overall, 38.7% of patients experienced RINV Previous chemotherapy increased risk of symptoms 0 10 20 30 40 50 VomitingNausea Previous chemotherapy No chemotherapy Patients (%) 22.1% 45.6% 15.1% 33.1% p=0.028 p=0.003 IGARR. Int J Radiat Oncol Biol Phys 1999;44:619–25

27. Duration of nausea and vomiting following radiotherapy The symptoms of RINV can last several hours after therapy 1 0 10 20 30 40 50 60 0 90120150180210240270300330360 Duration of symptoms (min) Patients experiencing nausea and vomiting (%) Upper hemibody (n=88) Lower hemibody (n=101) 1. Danioux et al. Clin Radiol 1979;30:581–4

28. Kytril has a 24-hour duration of action Kytril has ‘insurmountable’ 5HT 3 receptor binding 210210 Episodes/hour 04812162024 Time after chemotherapy administration (hours) First-day early-onset emesis First-day late-onset emesis Cisplatin Cyclophosphamide Carboplatin Kytril Ondansetron 9 hours 4 hours

29. Addition of NK 1 receptor antagonists improves efficacy of standard antiemetic regimen Standard 5HT 3 /dex combination Triple combinationp value Poli-Bigelli et al. (n=523) 1 Day 1 complete response rate (%) 68.482.8<0.001 Overall 5-day response rate (%) 43.362.7<0.001 Hesketh et al. (n=521) 2 Overall 5-day response rate (%) 52.372.7<0.001 1. Poli-Bigelli et al. Cancer 2003;97:3090–8 2. Hesketh et al. J Clin Oncol 2003;21:4112–9

30. Kytril effective in combination with steroids and NK 1 receptor antagonists Combination of 5HT 3 receptor antagonist and dexamethasone improves emetic control but delayed emesis still problematic Addition of neurokinin 1 (NK 1 ) receptor antagonists to 5HT 3 /dexamethasone extends emetic control –triple combination is now standard of care Emetic potential of therapy Acute emesisDelayed emesis High 5HT 3 + Dex + NK 1 Dex + NK 1 Moderate5HT 3 + DexDex LowDex + metoclopramide– International anti-emetic guidelines † † Adapted from Multinational Association for Symptom Control in Cancer

31. Conclusions The 5-HT 3 -receptor antagonists are effective for the treatment of RINV Kytril (granisetron) –effective in refractory patients –more effective than ‘conventional’ antiemetics –at least as effective as ondansetron –well tolerated –once-daily dosing –low risk for drug-drug interactions –no cardiovascular warning